These studies will test our hypothesis that a state independent, genetically influenced increase in muscarinic supersensitivity exists in patients with major affective illness. Two different methods will be used: (1) The cholinergic REM Induction Test (CRIT). In this test, the latency is measured to the onset of REM sleep following an infusion of either placebo or arecoline, a muscarinic agonist, during the second NREM period. (2) Direct measurements of muscarinic receptors, utilizing tritriated quinichidinyl benzilate (3H-QNB), on fibroblasts grown from a skin biopsy. Both methods will be used to study the following groups of subjects: (1) euthymic, unmedicated patients with bipolar and unipolar affective illness, as well as normal controls. (2) Male students and nonacademic staff at UCSD who have been identified as being at risk for affective illness on the basis of a prior history of affective illness, a family history of affective illness, or both. Control subjects with neither a personal nor a family history will be studied. (3) First degree family members of patients with affective illness and family members with and without a personal history of affective illness will be compared with each other and with the proband, who has a short response latency on the CRIT. These studies will address the following questions: (1) Is the response on the CRIT correlated with QNB estimates of muscarinic receptor binding on fibroblasts? (2) Can we replicate our earlier findings that the CRIT identifies euthymic patients with bipolar illness, and extend it to unipolar patients? (3) Can we replicate the preliminary findings of Nadi et al (in press) that muscarinic receptor binding is elevated in patients with affective illness and their first degree relatives? (4) Can either or both of these methods be used as a marker of vulnerability for affective illness? In addition, we wish to explore the possibility of using the CRIT during daytime sleep studies. If it were shown that this were feasible, it would increase the utility of the method. These studies offer new ways of assessing vulnerability and pathophysiological mechanisms in patients with affective illness, with theoretical and clinical implications.